Search

To investigate the penetrance of MYOC gene mutation in primary open-angle glaucoma (POAG) through systematic review and meta-analysis. To explore the factors affecting the penetrance of MYOC and provide evidence-based medical evidence for clinical work. We searched all studies that reported the penetrance of MYOC mutation in PubMed, Embase, Web of Science, and Chinese databases including Wanfang, CNKI (China National Knowledge Infrastructure), and CBM (China Bio-Med). Random effects meta-analysis was conducted to estimate the penetrance of MYOC mutation in POAG. Fifty-two studies were included in this analysis after screening. Meta-analysis of the penetrance of MYOC mutation showed that the penetrance of MYOC mutation in POAG was 60% (95% CI: 51.0% to 68.0%) and the penetrance of MYOC mutation in POAG and suspected POAG was 68% (95% CI: 60.0% to 75.0%). The penetrance of MYOC mutation increases with age. Among Caucasians, Asians, and Africans, the penetrance of MYOC mutation in POAG was 55%, 71%, 54%, respectively, and the penetrance of MYOC mutation in POAG and suspected POAG was 64%, 83%, and 57%, respectively. Besides, the penetrance of different MYOC mutation sites was significantly discrepant. The penetrance of MYOC mutation in POAG ranged from 10.3% to 100% depending on the mutation sites. Some MYOC mutation sites have a certain population specificity, which is only pathogenic in Caucasians or Asians. The penetrance of MYOC mutation in POAG showed significant differences due to different mutation sites. The penetrance increased with the accrescent of age. Ethnic difference was an important factor affecting the penetrance of MYOC mutation. Knowing the rules and influencing factors of the penetrance of MYOC mutations is significant for the assessment of the risk of POAG in carriers with the MYOC mutation.

Lithium niobate (LiNbO3, LN) devices play critical roles in quantum information processing. However, for special applications like quantum key distribution (QKD), the characteristics of materials and devices and their impact on practical systems must be intensively inquired. For the first time, we reveal that the photorefractive effect in LN can be utilized as a potential loophole to carry out malicious attacks by the eavesdroppers. We take a commercial LN-based variable optical attenuator as an example to demonstrate the method we named Induced-photorefractive attack (IPA) and propose two techniques to enable controllable attacks. Our results show that eavesdroppers can fulfill an efficient source-side attack by injecting an optimized irradiation beam with only several nanowatts, which is realistic when accessing commercial fiber channels. These measure and techniques can be employed for all individual and on-chip LN devices and initially explored a new security branch for system design and standardization of real-life QKD.

Objective Acute pancreatitis (AP) is a common and unpredictable disease. Severity stratification and prognostic prediction play an important role in reducing the mortality of AP and improving its prognosis in the early stage. We aimed to establish a clinical prediction model by logistic regression analysis visualized by nomogram. Methods A total of 497 patients with AP in the Nanfang Hospital, Southern Medical University between January 2015 and January 2018 were retrospectively collected. 497 patients were randomly (ratio = 7:3) divided into the training cohort (N = 347) and the validation cohort (N = 147), and both cohorts were divided into non-severe acute pancreatitis (non-SAP) and SAP groups. Univariate and multivariate logistic regression analysis were used to identify the factors associated with the severity of AP. Based on multivariate logistic regression analysis, nomogram was established and validated. The performance, discrimination, and calibration of nomogram were conducted. Decision curve analysis was used to evaluate the net benefits and clinical usefulness of the prediction model. Result Multivariate logistic regression analysis showed that alcohol use, hyperlipidemia, gender, hypertension, ionized serum calcium and serum albumin were independent risk factors for SAP. The individualized nomogram showed good discrimination both in the training cohort (area under the receiver operating characteristic curve [AUC], 0.782) and in the validation cohort (AUC, 0.764) with good calibration. Decision curve analysis demonstrated that in terms of clinical usefulness, the nomogram was found to have some clinical values and can be used in clinical practice. Conclusion The proposed nomogram based on easy-to-obtain features are of high efficacy in predicting SAP patients, which may facilitate clinical decision-making.

In chip-based quantum key distribution (QKD) systems, the non-ideal quantum state preparation due to the imperfect electro-optic phase modulators (EOPM) decreases the secret key rate and introduces potential vulnerabilities. We propose and implement an on-chip transmittance-invariant phase modulator (TIPM) to solve this problem. Simulated and experimental results show that TIPM can eliminate the correlation between phase, intensity, and polarization of quantum states caused by phase-dependent loss. The design can tolerate a significant fabrication mismatch and is universal to multi-material platforms. Furthermore, TIPM increases the modulation depth achievable by EOPMs in standard process design kit (PDK). The proposal of TIPM can improve the practical security and performance of the chip-based QKD systems.

Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Phospholipid metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA), and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analyze the proportion of pancreatic macrophages. Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated phospholipid pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulates phospholipid metabolism. Our study indicates that the acinar Atp8b1/LPC pathway acts as an important “find-me” signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1, and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

Background Noninflammatory clearance of dying cells by professional phagocytes, termed efferocytosis, is fundamental in both homeostasis and inflammatory fibrosis disease but has not been confirmed to occur in chronic pancreatitis (CP). Here, we investigated whether efferocytosis constitutes a novel regulatory target in CP and its mechanisms. Methods PRSS1 transgenic (PRSS1Tg) mice were treated with caerulein to mimic CP development. Sphingomyelin metabolite profiling and epigenetic assays were performed with PRSS1Tg CP models. The potential functions of Atp8b1 in CP model were clarified using Atp8b1-overexpressing adeno-associated virus, immunofluorescence, enzyme-linked immunosorbent assay(ELISA) and lipid metabolomic approaches. ATAC-seq combined with RNA-seq was then used to identify transcription factors binding to the Atp8b1 promoter, and ChIP-qPCR and luciferase assays were used to confirm that the identified transcription factor bound to the Atp8b1 promoter, and to identify the specific binding site. Flow cytometry was performed to analysis proportion of pancreatic macrophages. Results Decreased efferocytosis with aggravated inflammation was identified in CP. The lysophosphatidylcholine (LPC) pathway was the most obviously dysregulated sphingomyelin pathway, and LPC and Atp8b1 expression gradually decreased during CP development. H3K27me3 ChIP-seq showed that increased Atp8b1 promoter methylation led to transcriptional inhibition. Atp8b1 complementation substantially increased the LPC concentration and improved CP outcomes. Bhlha15 was identified as a transcription factor that binds to the Atp8b1 promoter and regulate sphingomyelin metabolism. Conclusion The acinar Atp8b1/LPC pathway acts as an important “find-me” signal for macrophages and plays a protective role in CP, with Atp8b1 transcription promoted by the acinar cell-specific transcription factor Bhlha15. Bhlha15, Atp8b1 and LPC could be clinically translated into valuable therapeutic targets to overcome the limitations of current CP therapies.

Background Early diagnosis and treatment of chronic pancreatitis (CP) are limited. In this study, St13, a co-chaperone protein, was investigated whether it constituted a novel regulatory target in CP. Meanwhile, we evaluated the value of micro-PET/CT in the early diagnosis of CP. Methods Data from healthy control individuals and patients with alcoholic CP (ACP) or non-ACP (nACP) were analysed. PRSS1 transgenic mice (PRSS1Tg) were treated with ethanol or caerulein to mimic the development of ACP or nACP, respectively. Pancreatic lipid metabolite profiling was performed in human and PRSS1Tg model mice. The potential functions of St13 were investigated by crossing PRSS1Tg mice with St13−/− mice via immunoprecipitation and lipid metabolomics. Micro-PET/CT was performed to evaluate pancreatic morphology and fibrosis in CP model. Results The arachidonic acid (AA) pathway ranked the most commonly dysregulated lipid pathway in ACP and nACP in human and mice. Knockout of St13 exacerbated fatty replacement and fibrosis in CP model. Sdf2l1 was identified as a binding partner of St13 as it stabilizes the IRE1α-XBP1s signalling pathway, which regulates COX-2, an important component in AA metabolism. Micro-PET/CT with 68Ga-FAPI-04 was useful for evaluating pancreatic morphology and fibrosis in CP model mice 2 weeks after modelling. Conclusion St13 is functionally activated in acinar cells and protects against the cellular characteristics of CP by binding Sdf2l1, regulating AA pathway. 68Ga-FAPI-04 PET/CT may be a very valuable approach for the early diagnosis of CP. These findings thus provide novel insights into both diagnosis and treatment of CP.

Purpose Glucose metabolism underpins diabetic cataracts (DCs), but the relationship between the two remains unclear. Here, we tested the aqueous humour (AH) of patients with DCs to elucidate glucose metabolite levels. Methods In this study, aqueous humour (AH) samples were collected preoperatively from DC eyes (n = 37) and age-related cataract eyes (n = 37) from 74 patients (74 eyes) undergoing uncomplicated cataract surgery. The content of glucose, pyruvate, L-lactate were detected by biochemical methods and advanced glycation end-products (AGEs) was detemined using enzyme-linked immunosorbent assay (ELISA) technique. Furthermore, the ratios of glucose/pyruvate and L-lactate/pyruvate in the AH were calculated. In addition, we calculated the correlation between glucose levels and AGEs in the AH. Results The concentrations of glucose, pyruvate and AGEs in the DC group were higher than those in the control group. Significantly lower levels of L-lactate in the AH were found in the DC group. We calculated the glucose/pyruvate ratio and the L-lactate/pyruvate ratio in the AH, which showed that glucose metabolism was changed in the AH from DC patients. Interestingly, we observed that AGEs in the AH were significantly correlated with increased anterior chamber glucose permeability. A stronger correlation was found in the subgroups of male patients, younger patients, and patients with poor glycaemic control status. Conclusions Comparison of the levels of glucose metabolism-related products in the AH in the DC group highlight a potential pathological mechanism for DC from a glucose metabolism perspective. The findings indicated an alteration in the metabolic pathways of energy metabolism and amino acids in the AH of DC patients.

Accumulating data manifest that long non-coding RNA (lncRNAs) are involved in all kinds of neurodegenerative disorders, consisting of the onset and progression of Alzheimer’s disease (AD). The study was for the research of the mechanism of lncRNA H19 (H19) in viability and apoptosis of PC12 cells induced by Aβ(25-35) in a cellular model of AD with the regulation of microRNA (miR)-129 and high mobility group box-1 protein (HMGB1). An AD cellular model of PC12 cells was established using Aβ(25-35). The Aβ(25-35)-induced PC12 cells were transfected with si-H19 or miR-129 mimic to figure their roles in cell viability,apoptosis, mitochondrial membrane potential dysfunction and oxidative stress in AD. Luciferase reporter assay and RNA-pull down assay were employed for verification of the binding relationship between H19 and miR-129 and the targeting relationship between miR-129 and HMGB1. An AD mouse model was induced and brain tissues were collected. H19, miR-129 and HMGB1 were detected in Aβ(25-35)-treated cells and brain tissues of AD mice. Elevated H19, HMGB1 and decreased miR-129 were found in Aβ(25-35)-treated PC12 cells as well as in brain tissues of AD mice. Silenced H19 or elevated miR-129 promoted viability, inhibited apoptosis, prevented mitochondrial membrane potential dysfunction and decreased oxidative stress in Aβ(25-35)-treated PC12 cells. H19 could specifically bind to miR-129. MiR-129 specifically suppressed HMGB1 expression. This study suggests that silenced H19 and up-regulated miR-129 accelerates viability and represses apoptosis of PC12 cells stimulated by Aβ(25-35) in AD, which is beneficial for AD treatment.

Background: Synchronous double primary cancer consisting of hepatocellular carcinoma (HCC) and appendiceal mucinous adenocarcinomas has not been reported in the world so far. Liver metastasis of digestive tract tumor is so common that it is easy to ignore the existence of double primary cancer in the digestive system. Appendiceal malignant tumor itself is easy to be misdiagnosed or missed. For the better understanding of HCC and appendiceal mucinous adenocarcinomas, the information of our recent case has been summarized.Case presentation: A 58-year-old man was admitted with repeated upper abdominal pain for one week. Imaging examination and liver biopsy pathology were diagnosed as hepatocellular carcinoma. Colonoscopy showed no obvious organic lesions in the terminal ileum and the whole large intestine. We had anatomical resection of S5, S6 segment of liver. At the same time, two suspicious lesions in the right liver were ablated by microwave. But at the end of the operation, we accidentally found a hard mass about 3cm x 3cm in size at the end of the appendix. And the rapid pathological results showed appendiceal adenocarcinoma, so we had a right hemicolectomy. So far, the diagnosis of the patient was changed to synchronous double primary cancer consisting of HCC and appendiceal mucinous adenocarcinomas.Conclusions: It is the first time we report a case of synchronous double primary hepatic cancer consisting of HCC and appendiceal mucinous adenocarcinomas in the world. Due to the rarity and unspecific clinical features, it is extremely challenging to be diagnosed preoperatively. It requires us to have a more comprehensive understanding of the patient's medical history, careful physical examination and comprehensive exploration of the abdominal cavity during the operation, so as to avoid missed diagnosis. Patients with HCC and appendiceal mucinous adenocarcinomas are generally associated with poor prognosis. It needs we put forward new countermeasures for the new question.

Background: Pancreatic cancer (PC) is prevalent among malignant tumors with poor prognosis and lacks efficient therapeutic strategies. Endoplasmic reticulum (ER) stress and apoptosis are associated with chronic inflammation and cancer progression. However, the prognostic value of ER stress-related, and apoptosis-related genes in PC remains to be further elucidated. Our study aimed at confirming the prognostic values of the ER stress-related genes, ATF6, EMC6, XBP1, and CHOP, and the apoptosis-related gene, APAF1, in PC patients.Methods: Gene Expression Profiling Interactive Analysis 2 (GEPIA2) was used to evaluate prognosis value of ATF6, EMC6, XBP1, CHOP, and APAF1 in PC. Clinical data from 69 PC patients were retrospectively analyzed. Immunohistochemistry, Western blotting, and qRT-PCR were used for the assessment of gene or protein expression. The cell counting kit-8 (CCK-8) and the Transwell invasion assays were, respectively, used for the assessment of the proliferative and invasive abilities of PC cells. The prognostic values of ATF6, XBP1, CHOP, EMC6, and APAF1 in PC patients were evaluated using Kaplan–Meier and Cox regression analyses.Results: XBP1 and CHOP expressions were not associated with PC recurrence-free survival (RFS), overall survival (OS) and disease-specific survival (DSS). ATF6 upregulation and EMC6 and APAF1 downregulations significantly correlated with the poor RFS, OS, and DSS of PC patients. ATF6 promoted PC cell proliferation and invasion, while EMC6 and APAF1 inhibited these events.Conclusion: ATF6 upregulation and EMC6 and APAF1 downregulations may be valid indicators of poor prognosis of PC patients. Moreover, ATF6, EMC6, and APAF1 may constitute potential therapeutic targets in PC patients.

Background/aims Previous study has shown a positive relationship between the hepatitis B virus (HBV) or hepatitis C virus (HCV) infection and cholangiocarcinoma (CCA); however, their correlation with different anatomical sites of CCA (i.e. ICC and ECC) has not been revealed. This study aims to evaluate the association of HBV or HCV infection with CCA, including the intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC), and to determine the roles of α-1 fetoprotein (AFP), CA19-9, and lymph node involvement in CCA with HBV infection. Materials and methods Relevant studies published between 2004 and 2016 were systematically searched and retrieved from PubMed, SpringerLink, and Science Direct using key terms such as "cholangiocarcinoma", "bile duct cancer", "extrahepatic cholangiocarcinoma", and "intrahepatic cholangiocarcinoma". The demographic, clinical, and laboratory data were extracted from the included studies, and the meta-analysis was performed using RevMan and STATA 11.0 software. Results A total of 13 studies with CCA matched the inclusion criteria in this meta-analysis, including 7,113 CCA patients and 24,763 controls. This meta-analysis showed that the HBV or HCV infections can significantly increase the risk of CCA, including ICC and ECC. In addition, the higher levels of AFP, lower levels of CA19-9, and lymph node involvement were detected in the CCA patients with HBV infection as compared to those without. Conclusion The HBV and HCV infections significantly increased the risk of CCA, as well as ICC and ECC. The involvement of AFP, CA19-9, and lymph nodes may play an important role in the diagnosis of CCA.

Acute pancreatitis (AP) is a severe pancreatic disorder that remains associated with high mortality due to a lack of effective drugs and management strategies. This study aimed to investigate the molecular pathogenic mechanisms of AP involving p53 and endoplasmic reticulum (ER) stress pathways. Expression of PRSS1 and p53 in human AP tissues was detected by immunohistochemistry and Western blotting. AP was induced with caerulein in humanized PRSS1 transgenic mice, and its severity was verified by histological imaging, evaluation of edema, serum amylase, and trypsin activity assays. A transferase-mediated d-UTP nick end-labeling assay was performed to evaluate acinar cell apoptosis associated with AP. The expression of ER stress genes was assessed by quantitative RT-PCR (qRT-PCR) and Western blotting. PRSS1 and p53 were highly expressed in human AP tissues. Expression of human PRSS1 in caerulein-treated mice induced significant acinar cell apoptosis and AP progression. P53 knockout significantly suppressed AP progression in humanized PRSS1 transgenic mice. The ER stress pathway was activated by PRSS1 and mediated the progression of AP in mouse pancreatic tissues. Application of a p53 inhibitor effectively ameliorated caerulein-induced AP in PRSS1 transgenic mice, while a p53 activator promoted the progression of AP. P53, which was activated by the ER stress pathway, promoted the progression of AP in mice expressing PRSS1 by inducing acinar cell apoptosis.

AIM: To investigate potential gene changes in trabecular meshwork (TM) induced by dexamethasone (DEX) in steroid-induced glaucoma (SIG). METHODS: The expression data of 24 cases from a public functional genomics data were sorted to identify the mechanisms of action of DEX on the TM. The relationships of the differentially expressed genes (DEGs) were enriched using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. In addition, the hub genes were screened by the Search Tool for the Retrieval of Interacting Genes Database (STRING) and Cytoscape tools. Finally, human TM cells (HTMCs) were treated with DEX to preliminarily explore the function of hub genes. RESULTS: Totally 47 DEGs, including 21 downregulated and 26 upregulated genes were identified. The primary enriched results of the DEGs consisted of inflammatory response, extracellular matrix (ECM), negative regulation of cell proliferation, TNF signalling pathway and the regulation of tryptophan channels by inflammatory mediators. Subsequently, pro-melanin-enriched hormone (PMCH) and Bradykinin B1 receptor (BDKRB1) were screened as hub genes. It is verified in GSE37474 data set. Western blot and quantitative real-time polymerase chain reaction (qPCR) results showed that protein and RNA expression levels of BDKRB1 were significantly decreased after DEX treatment, while PMCH was not significantly changed. CONCLUSION: BDKRB1 may be a key gene involved in SIG onset, providing a suitable therapeutic target for improving the prognosis of SIG patients.

To investigate the penetrance ofWe searched all studies that reported the penetrance ofFifty-two studies were included in this analysis after screening. Meta-analysis of the penetrance ofThe penetrance of

Generation of a promising antioxidative reagent with superior biocompatibility is urgently needed to remedy spinal cord injuries (SCI), repair the damaged neurons and restrain the secondary injuries caused by inflammation-induced oxidative stress. Inhibitory elements in the injury sites and necessitous inherent neural regeneration ability were major challenges for functional recovery after spinal cord injuries. We here developed a highly bioactive iridium complex (IrFPHtz) with enhanced antioxidative activities and improved SCI therapeutic efficacy. Both in vivo and in vitro, IrFPHtz has exhibited neuroprotective and anti-inflammatory properties. Mechanically, IrFPHtz directly targets SOD1 and upregulates the expression of SOD1 to eliminate the excess Reactive Oxygen Species (ROS) production induced by SCI, and thus protecting neuron cells from further damage. As a result, IrFPHtz safeguarded the neurons and myelin sheaths against trauma, lessened glial scar conformations and facilitated the repair of neurons and long axon expansion in the glial scar. Furthermore, IrFPHtz significantly ameliorated the behavioral functions of SCI mice and promoted a satisfactory curative effect. Therefore, this study sheds light on a novel method for SCI treatment using IrFPHtz as a potential drug and implicates the clinical significance of metal complexes in diseases featuring with upregulated ROS species.

PURPOSE Few authors have studied applying the laparoscopic approach in patients with previous upper abdominal operations, but no comparison has been made between laparoscopic and open approaches in patients with previous upper abdominal operations. This article aims to introduce surgical techniques and details in treatment to surgeons specialized in minimally invasive surgery. MATERIALS AND METHODS From January 2010 to January 2018, 460 eligible patients were divided into 3 groups and analyzed retrospectively. Group A: patients with a history of upper abdominal operations who underwent laparoscopy (n=124); group B: patients without a history of upper abdominal operations who underwent laparoscopy (n=140); and group C: patients with a history of upper abdominal operations who underwent an open operation (n=196). Group A was the experimental group; groups B and C served as the control groups. RESULTS No significant difference was found between groups A and B. Significant differences were found between groups A and C in estimated blood loss (258.3±67.2 vs. 424.7±103.7 mL, P

Infusing CRISPR/donor-loaded adeno-associated viral vectors (AAV/CRISPR) could enable in vivo hepatic gene editing to remedy hemophilia B (HB) with inherited deficiency of clotting factor IX (FIX). Yet, current regimens focus on correcting HB with simple mutations in the coding region of the F9, overlooking those carrying complicated mutations involving the regulatory region. Moreover, a possible adverse effect of treatment-related inflammation remains unaddressed. Here we report that a single DNA cutting-mediated long-range replacement restored the FIX-encoding function of a mutant F9 (mF9) carrying both regulatory and coding defects in a severe mouse HB model, wherein incorporation of a synthetic Alb enhancer/promoter-mimic (P2) ensured FIX elevation to clinically meaningful levels. Through single-cell RNA sequencing (scRNA-seq) of liver tissues, we revealed that a subclinical hepatic inflammation post-AAV/CRISPR administration regulated the vulnerability of the edited mF9-harboring host cells to cytotoxic T lymphocytes (CTLs) and the P2 activity in a hepatocytic subset-dependent manner via modulating specific sets of liver-enriched transcription factors (LETFs). Collectively, our study establishes an AAV/CRISPR-mediated gene-editing protocol applicable to complicated monogenetic disorders, underscoring the potentiality of improving therapeutic benefits through managing inflammation.

Infusing CRISPR/donor-loaded adeno-associated viral vectors (AAV/CRISPR) could enable in vivo hepatic gene editing to remedy hemophilia B (HB) with inherited deficiency of clotting factor IX (FIX). Yet, current regimens focus on correcting HB with simple mutations in the coding region of the F9, overlooking those carrying complicated mutations involving the regulatory region. Moreover, a possible adverse effect of treatment-related inflammation remains unaddressed. Here we report that a single DNA cutting-mediated long-range replacement restored the FIX-encoding function of a mutant F9 (mF9) carrying both regulatory and coding defects in a severe mouse HB model, wherein incorporation of a synthetic Alb enhancer/promoter-mimic (P2) ensured FIX elevation to clinically meaningful levels. Through single-cell RNA sequencing (scRNA-seq) of liver tissues, we revealed that a subclinical hepatic inflammation post-AAV/CRISPR administration regulated the vulnerability of the edited mF9-harboring host cells to cytotoxic T lymphocytes (CTLs) and the P2 activity in a hepatocytic subset–dependent manner via modulating specific sets of liver-enriched transcription factors (LETFs). Collectively, our study establishes an AAV/CRISPR-mediated gene-editing protocol applicable to complicated monogenetic disorders, underscoring the potentiality of improving therapeutic benefits through managing inflammation.

Objective: Alzheimer’s disease (AD) is a common neurodegenerative disease. This study was designed to investigate the roles of lncRNA NEAT1/miR-27a-3p axis in AD. Methods: Amyloid protein was used to treat SH-SY5Y cells and rats to construct AD model. RT-qPCR was used to quantify lncRNA NEAT1 and micro-27a-3p in AD model cells. Western blot was used to determine the β-amyloid-precursor-protein-cleaver-enzyme 1 (BACE1), amyloid, Tau protein and its phosphorylation, Caspase 3 protein and its lytic cell protein and amyloid precursor protein (APP). Flow cytometry was used to detect apoptosis. The cell activity was detected by CCK-8. The lncRNA NEAT1 and miR-27a-3p inhibition or over-expression vectors were constructed. The dual luciferase reporter gene and RNA pull-down assay were used to detect the targeting relationship between lncRNA NEAT1 and micro-27a-3p. The cognitive function of rats was tested by water maze. Results: After being induced by amyloid protein, lncRNA NEAT1 was up-regulated while micro-27a-3p was down-regulated in SH-SY5Y cells. Apoptosis rate was increased and cell activity was decreased. Amyloid protein, BACE1 protein, APP protein, Tau protein and its phosphorylation, Caspase 3 protein and its lytic cell protein were up-regulated. Down-regulation of lncRNA NEAT1 or up-regulation of micro-27a-3p could reduce cell apoptosis, increase cell activity, down-regulate amyloid protein, BACE1 protein, APP protein, Tau protein and its phosphorylation, and up-regulate caspase 3 protein and its lysate protein. Dual luciferase reporter gene assay and RNA pull-down experiments revealed that micro-27a-3p was the target gene of lncRNA NEAT1. Down-regulation of micro-27a-3p could offset the changes caused by LncRNA NEAT1. AD caused cognitive dysfunction in rats, which was improved by down-regulation of lncRNA NEAT1. Conclusion: lncRNA NEAT1 regulates the development of AD by down-regulating micro-27a-3p.

In this study, we analyzed the mechanism of hydroxysafflor yellow A (HSYA) for treating ischemic stroke (IS) based on network pharmacology tools, and verified the kernel targets via animal experiments. The targets of HSYA were collected via PharmMapper server and the IS-related targets were searched using Genecards, Online Mendelian Inheritance in Man, Therapeutic Target, and Disgenet databases. The targets identified from the above two steps were overlapped to acquire candidate targets involved in the effects of HSYA for treating IS. Subsequently, the Database for Annotation, Visualization, and Integrated Discovery was used for gene ontology analysis and the Kyoto encyclopedia of genes and genomes pathway analysis. Cytoscape 3.7.1 was applied to establish the component-target-pathway network. Potential core targets were obtained by protein-protein interaction analysis. Furthermore, Autodock Vina was used to identify core genes, and animal experiments was used to verify the expression level of core genes. On the basis of the modified neurologic severity score and the results of 2,3,5-Triphenyltetrazolium chloride and Hematoxylin-eosin staining, we confirmed that HSYA reduced the infarct volume in rats and protected neuronal cells in the hippocampal region after IS. Western blot and immunohistochemical staining showed that HSYA increased the expression of epidermal growth factor receptor, hypoxia inducible factor 1 alpha, and endothelial nitric oxide synthase (P 0.05). The effects of HSYA on IS are mediated through several targets and pathways related to the regulation of oxidative stress and the renewal of cell and blood vessels while improving post-ischemic brain impairment.

Objective Studies have focused on the functions of microRNAs (miRNAs) in Alzheimer’s disease (AD), but not much on miR-16-5p. Hence, this study intends to unearth the mechanism of AD, mainly focusing on miR-16-5p/B-cell translocation gene 2 (BTG2) axis. Methods APPswe/PS1dE9 mice were injected with depleted BTG2 and/or restored miR-16-5p vectors into the third ventricle to explore their roles in neurological function, neuronal damage, autophagy and apoptosis in AD mice. In vitro cultured hippocampal neurons were transfected with depleted BTG2 and/or restored miR-16-5p vector to interpret their functions in neuronal viability and apoptosis. MiR-16-5p and BTG2 expression in hippocampal tissues and neurons were detected. Results Lower miR-16-5p and higher BTG2 expression levels were found in hippocampal tissues and neurons. MiR-16-5p up-regulation or BTG2 down-regulation improved neurological function and neuronal damage and inhibited neuronal autophagy and apoptosis in AD mice. Restored miR-16-5p or depleted BTG2 restrained neuronal viability and apoptosis in vitro. Conclusion Our study reveals that restored miR-16-5p or depleted BTG2 protects neurological function and suppresses neuronal autophagy and apoptosis in AD mice, which renews a novel guide toward AD treatments from the perspective of miR-16-5p/BTG2 axis.

To investigate the efficacy and safety of lycopene in the treatment of BPH with lower urinary tract symptoms (LUTS).Totally, 127 BPH patients with LUTS were treated with oral lycopene tablets at 500 mg bid in the Department of Andrology of Jinling Hospital from January 2018 to January 2019. At 8 and 16 weeks of medication, we compared the IPSS, quality of life (QOL) score, prostate volume, PSA level, maximum urinary flow rate (Qmax), postvoid residual urine volume (PVR) and the incidence of adverse reactions before and after treatment.A total of 120 patients completed the treatment. Compared with the baseline, significant improvement was observed after 8 weeks of medication in the IPSS (［18.42 ± 4.59］ vs ［14.13 ± 4.51］, P0.01) and QOL score (［4.34 ± 1.37］ vs ［3.14 ± 1.25］, P0.01), and even more significant at 16 weeks in the IPSS (［18.42 ± 4.59］ vs ［10.29 ± 3.61］, P0.01), QOL score (［4.34 ± 1.37］ vs ［2.17 ± 1.35］, P0.01), PSA (［3.87 ± 3.14］ vs ［2.90 ± 3.07］ μg/L, P0.01), Qmax (［10.62 ± 2.08］ vs ［14.15 ± 3.66］ ml/s, P0.01) and PVR (［35.88 ± 15.33］ vs ［18.36 ± 13.09］ ml, P0.01), but there was no statistically significant difference in the prostate volume before and after treatment (［39.85 ± 10.22］ vs ［38.16 ± 10.12］ ml, P0.05), and no adverse reactions in any of the patients.Lycopene has a good therapeutic effect on BPH with LUTS, which can significantly improve the patients' quality of life without causing adverse reactions.

To detect the contents of prostaticexosomal protein (PSEP) in the first- and mid-stream urine and assess their clinical value in the diagnosis of chronic prostatitis (CP).This study included358 male outpatientsat Nanjing General Hospital from November 2017 to May 2018, 269 diagnosed with and the other 89 without CP. Wemeasured the contents of PSEP in the first- and mid-stream urine samples collected from the subjectsby ELISA anddetermined the sensitivity and specificity, and total coincidence rate ofthe PSEPcontents in the diagnosis of CP. Using the ROC curve, we compared the PSEP levels in the two different urine samples and the results of diagnosis of CPbetween the PSEP detection method and clinical diagnostic criteria.No statistically significant difference was observed between the contents of PSEP in the first- and mid-stream urine samples (［3.82 ± 3.74］ vs ［3.77 ± 3.90］ ng/ml, P = 0.46). In the diagnosis of CP, the PSEP contents in the first- and mid-stream urine samples manifested a sensitivity of 81.41% vs 86.99%, a specificity of 89.89% vs 88.76%, and a total coincidence rate of 83.52% vs 87.43%.Both the content of PSEP in the first-stream and that in the mid-stream urine can be used as auxiliarydiagnostic indicators of chronic prostatitis, bothwith high sensitivity and specificity.

Background: Treatment of acute pancreatitis (AP) and chronic pancreatitis (CP) remains problematic due to a lack of knowledge about disease-specific regulatory targets and mechanisms. The purpose of this study was to screen proteins related to endoplasmic reticulum (ER) stress and apoptosis pathways that may play a role in pancreatitis. Methods: Human pancreatic tissues including AP, CP and healthy volunteers were collected during surgery. Humanized PRSS1 transgenic mice were constructed and treated with caerulein to mimic the development of human AP and CP. Potential regulatory proteins in pancreatitis were identified by proteomic screen using pancreatic tissues of PRSS1 transgenic AP mice. Adenoviral shRNA-mediated knockdown of identified proteins, followed by functional assays was performed to validate their roles. Functional analyses included transmission electron microscopy for ultrastructural analysis; qPCR, western blotting, immunohistochemistry, immunofluorescence and immunoelectron microscopy for assessment of gene or protein expression, and TUNEL assays for assessment of acinar cell apoptosis. Findings: Humanized PRSS1 transgenic mice could mimic the development of human pancreatic inflammatory diseases. EMC6 and APAF1 were identified as potential regulatory molecules in AP and CP models by proteomic analysis. 1) increased expression of EMC6 and APAF1 was observed in patient and mouse AP/CP tissues; 2) inhibition of the two proteins resulted in attenuation of apoptosis and inflammation; 3) inhibition of EMC6 was associated with decreased expression of APAF1, suggesting a potential mechanistic connectivity. Interpretation: EMC6 and APAF1 are strongly associated with pancreatitis development, and may represent therapeutic targets for the treatment of pancreatic inflammatory diseases. Funding Statement: The article is supported by Guangdong Science and Technology Planning Project (2019A030317018) & Scientific Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (CX2018N012) & Clinical Research Program of Nanfang Hospital, Southern Medical University (2018CR046) & College Students’ Innovative Entrepreneurial Training Plan Program (201812121128, 201812121263) & Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY011) & National Natural Science Foundation of China (81801487). Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: Written consent was obtained from each patient before the study, which were approved by the Ethics Committee of the Southern Medical University. The experimental operations were carried out in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the Institutional Animal Care and Use Committee of Southern Medical University.

A new and efficient approach for the N-arylation of 8-aminoquinoline amides with diaryliodonium salts has been developed. This chelation-assisted selective C–N cross-coupling reaction gave the desired N-arylated 8-aminoquinoline in moderate to good yields. In contrast to previous reports, no additional ligands and bases are used in this transformation. In addition, the anion of the diaryliodonium salt plays an important role in the success of the process.

Background: Non-fusion fixation is an effective way to treat lumbar degeneration. The present study evaluated the clinical effect analysis and radiographic outcomes of Isobar TTL system for two-segmental lumbar degenerative disease. Method: Forty-one patients with two-segmental lumbar degenerative disease who underwent surgical treatment by Isobar TTL dynamic stabilization system (n=20) and rigid system (n=21) from January 2013 to June 2017. The mean follow-up period was 23.6 (range 15–37) months. Clinical outcomes were evaluated by oswestry dysfunction index (ODI), visual analogue score (VAS) and modified Macnab. Radiographic evaluations included the height of intervertebral space and range of motion (ROM) of the operative segments and proximal adjacent segment. The intervertebral disc signal change was classified by the modified Pfirrmann grade and University of California at Los Angeles (UCLA) system. Results: The clinical outcomes including the ODI and VAS were significantly improved in two groups after operation, but the difference between two groups was not significant. In addition, the clinical efficacy of modified Macnab in two groups was similar too. Radiologic outcomes include height of intervertebral space, lumbar mobility and intervertebral disc signal. The height of intervertebral space of upper adjacent segments of L2/3 in the rigid group were significantly lower than those in the Isobar TTL group at the last follow-up. Furthermore, the number of fixed segment ROM of L3/4 in Isobar TTL group was significantly lower than pre-operation, suggesting that fixed segment ROMs in Isobar TTL group were limited. And, the ROM of upper adjacent segments of L2/3 in the last follow-up of rigid group increased significantly, while the ROM of L2/3 in Isobar TTL group haven’t changed after operation. At last, the incidence of adjacent segment degeneration was significantly greater in the rigid group than the Isobar TTL group according to modified Pfirrmann grading system and the UCLA system. Conclusion: Isobar TTL system could get a good clinical effect for treatment of two-segmental lumbar degenerative disease. Compared with rigid fixation, Isobar TTL system can get better radiographic outcomes and maintain the mobility of the stabilized segments with less influence on the proximal adjacent segment.

Interferometers are essential elements in classical and quantum optical systems. The strictly required stability when extracting the phase of photons is vulnerable to polarization variation and phase shift induced by environment disturbance. Here, we implement polarization-insensitive interferometers by combining silica planar light-wave circuit chips and Faraday rotator mirrors. Two asymmetric interferometers with temperature controllers are connected in series to evaluate the single-photon interference. Average interference visibility over 12 h is above 99%, and the variations are less than 0.5%, even with active random polarization disturbance. The experiment results verify that the hybrid chip is available for high-demand applications like quantum key distribution and entanglement measurement.

The dual transition metal-visible light photoredox catalysis for the synthesis of quinoline derivatives by using dioxygen as an oxygen source is developed. By using visible light, the direct oxidative cyclization of aromatic enamines with alkynes or alkenes can be achieved at mild conditions with an aid of copper or palladium catalysts, and a variety of multisubstituted quinoline derivatives could be obtained in good to moderate yields under mild reaction conditions.

An effective metal-free photoredox-mediated tandem addition/cyclization reaction of thiophenols or 1,2-diphenyldiselane with alkynes leads to 2,3-disubstituted benzothiophenes and benzoselenophenes. Blue light irradiation of the organic dye, Mes-Acr-Me + , initiates the photoredox catalysis. A series of functional groups could be tolerated under ambient conditions, and good to excellent yields were generated.

OBJECTIVES The aim of this study was to evaluate the role of parecoxib in patients with different severities of acute pancreatitis (AP). METHODS A total of 772 eligible patients with AP were divided into 4 groups: mild and moderately AP (MAP) treated with parecoxib (group A, n = 236), MAP without parecoxib treatment (group B, n = 453), severe AP (SAP) treated with parecoxib (group C, n = 28), and SAP without parecoxib treatment (group D, n = 55). Patients in group A were exactly matched with patients in group B by propensity score matching, similar to the matching between group C and group D. RESULTS The morbidity of abdominal infection in group A was significantly lower as compared with that in group B (P < 0.050). The progression of MAP to SAP significantly decreased in group A than group B (P < 0.050). No significant differences were observed between group C and group D. The risk factors independently related to the progression of MAP included alcoholic/high-fat dietary (P = 0.028) and parecoxib administration (P = 0.011). CONCLUSIONS Early administration of parecoxib could reduce the morbidity of complications among patients with MAP. Parecoxib may prevent the progression of MAP to SAP and improve its outcomes.

Chronic pancreatitis (CP) is a progressive, recurrent inflammatory disorder of the pancreas. Initiation and progression of CP can result from serine protease 1 (PRSS1) overaccumulation and the ensuing endoplasmic reticulum (ER) stress. However, how ER stress pathways regulate the development and progression of CP remains poorly understood. In the present study we aimed to elucidate the ER stress pathway involved in CP. We found high expression of the ER stress marker genes ATF6, XBP1, and CHOP in human clinical specimens. A humanized PRSS1 transgenic mouse was established and treated with caerulein to mimic the development of CP, as evidenced by pathogenic alterations, collagen deposition, and increased expression of the inflammatory factors IL-6, IL-1β, and TNF-α. ATF6, XBP1, and CHOP expression levels were also increased during CP development in this model. Acinar cell apoptosis was also significantly increased, accompanied by upregulated p53 expression. Inhibition of ATF6 or p53 suppressed the expression of inflammatory factors and progression of CP in the mouse model. Finally, we showed that p53 expression could be regulated by the ATF6/XBP1/CHOP axis to promote the development of CP. We therefore conclude that ATF6 signalling regulates CP progression by modulating pancreatic acinar cell apoptosis, which provides a target for ER stress-based diagnosis and treatment of CP.

Background: Acute pancreatitis is a severe pancreatic disorder that remains associated with high mortality due to a lack of effective drugs and management strategies. This study aimed to investigate the molecular pathogenic mechanisms of acute pancreatitis involving p53 and endoplasmic reticulum (ER) stress pathways. Methods: Expression of PRSS1 and p53 in human acute pancreatitis tissues was detected by immunohistochemistry and western blotting. Acute pancreatitis was induced with caerulein in humanized PRSS1 transgenic mice, and its severity was verified by histological imaging, evaluation of edema, and serum amylase and trypsin activity assays. A transferase mediated d-UTP nick end-labeling assay was performed to evaluate acinar cell apoptosis associated with acute pancreatitis. The expression of ER stress genes was assessed by quantitative RT-PCR (qRT-PCR) and western blotting. Results: PRSS1 and p53 were highly expressed in human acute pancreatitis tissues. Expression of human PRSS1 in caerulein-treated mice induced significant acinar cell apoptosis and acute pancreatitis progression. p53 knockout significantly aggravated acute pancreatitis progression in humanized PRSS1 transgenic mice. The ER stress pathway was activated by PRSS1 and mediated the progression of acute pancreatitis in mouse pancreatic tissues. Application of a p53 inhibitor promoted caerulein-induced acute pancreatitis in PRSS1 transgenic mice, while a p53 activator ameliorated the progression of acute pancreatitis. Conclusion: P53, which was activated by the ER stress pathway, suppresses the progression of acute pancreatitis in mice expressing PRSS1 by inducing acinar cell apoptosis. Funding: The article is supported by Scientific Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (CX2018N012) & Clinical Research Program of Nanfang Hospital, Southern Medical University (2018CR046) & Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education (LC2016PY011). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: All experimental procedures performed with mice were approved by the Institutional Animal Care and Use Committee of Southern Medical University.

In this paper, a Crank–Nicolson-type finite difference method is proposed for computing the soliton solutions of a complex modified Korteweg–de Vries (MKdV) equation (which is equivalent to the Sasa–Satsuma equation) with the vanishing boundary condition. It is proved that such a numerical scheme has the second-order accuracy both in space and time, and conserves the mass in the discrete level. Meanwhile, the resulting scheme is shown to be unconditionally stable via the von Nuemann analysis. In addition, an iterative method and the Thomas algorithm are used together to enhance the computational efficiency. In numerical experiments, this method is used to simulate the single-soliton propagation and two-soliton collisions in the complex MKdV equation. The numerical accuracy, mass conservation and linear stability are tested to assess the scheme’s performance.

A metal- and oxidant-free electrochemical synthesis of aryl sulfides was developed through a C–H sulfidation reaction of arenes and disulfides. Compared with traditional organic synthesis methods, this direct electrochemical approach efficiently generates aryl sulfides under catalyst- and oxidant-free conditions with the superiorities of wide substrate compatibility, mild reaction condition and waster free. At room temperature, various aryl thiols could be transformed smoothly in an undivided cell. Based on cyclic voltammetry (CV) and control experiments, the possible reaction mechanism was also proposed. The gram-scale synthesis emphasizes the practicability of this electrochemical strategy.

BFD model for predicating smoke temperature of large space building can accurately predict the temperature field distribution of the whole process of fire, but the shape coefficient of important parameters in the model is not comprehensive. In this paper, several important factors affecting BFD model had been discussed and the value of shape coefficient (w1/w2) in different fire scenarios had been given. Temperature field distribution under various condition had been gained through simulating more than 20 kinds of fire scenarios by FDS, then the appropriate value of w1/w2 had been determined by fitting of origin. Finding that the fire growth factor has a decisive effect on w1/w2, and same w1/w2 can be used in BFD model in different position below the ceiling under the same fire scenario. Meanwhile that building height and area have little impact on w1/w2 under H>6m or S>1500m2 had been validated again. Therefore, BFD model application has been greatly simplified and the temperature of BFD model using above w1/w2 are in accordance with the results of FDS simulating for large space building. Based on the results obtained, the possibility of applying BFD model into engineering field becomes very high.